Non-steroidal ligands for the estrogen receptor

Abstract

Prescribed herein are novel non-steroidal ligands for the estrogen receptor which possess tissue-dependent estrogenic and antiestrogenic activity as well as methods for making the same and their applications in treating a variety of disease states.

We claim: 
     
       1. A compound of Formula I: ##STR12## wherein R 1  is --(CH 2 ) n  CR 5  =CR 6  R 7  ; R 2  and R 3  are independently H, --CH 3 , --OH, --OCH 3 , --OCH 2  CH 3  or --CH(CH 3 ) 2  ;   R 4  is --CN, --NO 2 , --CH 3 , --CH 2  CH 3 , --CH 2  CH 2  --Y or --Y;   R 5  and R 6  are independently H, --C 1-4  alkyl, --C 2-4  alkenyl, --C 2-4  alkynyl, --X--C 1-3  alkyl, --X--C 2-4  alkenyl, --X--C 2-4  alkynyl or --Y;   R 7  is --CN, --C 1-4  alkyl--OH, --C(O)NR 10  R 11 , --C(O)NR 12  R 13 , --C(O)NHCH 2  R 12 , --C(NH 2 )(NOR 12 ), --S(O)R 12 , --S(O)(O)(OR 12 ), --S(O)(O)(NHCO 2  R 12 ), PO 3  R 12 , P(O)(NR 12  R 13 )(NR 12  R 13 ), --P(O)(NR 12  R 13 )(OR 14 ), --CONR 12  (CH 2 ) q  OCH 3 , --CONR 12  (CH 2 ) q  NR 8  R 9  or oxadiazole substituted with methyl;   R 8  and R 9  are independently hydrogen, --C 1-7  alkyl, --C 3-7  cycloalkyl, --O--C 1-7  alkyl, --C 1-7  alkyl-Y or phenyl;   R 10  and R 11  are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;   R 12 , R 13  and R 14  are independently H, --C 1-12  alkyl, --C 2-12  alkenyl, --C 2-12  alkynyl, --O--C 1-12  alkyl, --O--C 2-12  alkenyl, --O--C 2-12  alkynyl, --C 3-7  cycloalkenyl, --C 3-7  cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or --Y;   X is oxygen or sulfur;   Y is a halogen;   n is an integer selected from 0, 1 and 2;   q is an integer from 1-12.   
     
     
       2. A compound according to claim 1 wherein X is 0. 
     
     
       3. A compound according to claim 1 wherein R 2  and R 3  are independently selected from H, --OH and --OCH 3 . 
     
     
       4. A compound according to claim 4 wherein R 2  and R 3  are H. 
     
     
       5. A compound according to claim 1 wherein R 4  is either --CH 3 , --CH 2  CH 3  or --CH 2  CH 2  --Cl. 
     
     
       6. A compound according to claim 1 wherein R 5  and R 6  are independently H or --C 1-4  alkyl. 
     
     
       7. A compound according to claim 1 wherein R 8  and R 9  are independently hydrogen, --C 1-7  alkyl or --C 3-7  cycloalkyl. 
     
     
       8. A compound according to claim 2 wherein R 7  is --C(O)NR 10  R 11 , --C(O)NR 12  R 13 , --C(O)OR 12 , C(O)NHC(O)R 12 , --C(NH 2 )(NOR 12 ), --S(O)(O)(NHCO 2  R 12 ), PO 3  R 12 , --P(O)(NR 12  R 13 )(NR 12  R 13 ) or P(O)(NR 12  R 13 )(OR 14 ). 
     
     
       9. A compound according to claim 1 wherein R 12 , R 13  and R 14  are independently H, --C 1-12  alkyl or --C 2-12  alkenyl. 
     
     
       10. A compound according to claim 1 wherein R 7  is --C(O)OR 2  ; wherein R 12  and R 6  are hydrogen. 
     
     
       11. A compound according to claim 1 wherein n is zero. 
     
     
       12. A compound according to claim 1, wherein R 2 , R 3 , and R 5  are hydrogen, R 4  is --CH 2  CH 3 , R 7  is --C(O)NR 12  R 13  or --C(O)OR 12 , and n is zero. 
     
     
       13. A compound according to claim 12, wherein R 7  is --C(O)NR 12  R 13 . 
     
     
       14. A compound according to claim 12, wherein R 7  is --C(O)OR 12 . 
     
     
       15. A compound according to claim 1 wherein the compound is selected from one of the following: 3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-N,N-diethyl acrylamide;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-N,N-diethyl-2-methyl-acrylamide;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-but-2-enoic acid diethylamide;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-acrylic acid methyl ester;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-acrylonitrile;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-acrylic acid tert-butyl ester;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-acrylic acid;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-1-morpholin-4-yl-prop-2-en-1-one;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-N-(3-methoxy-propyl)-acrylamide;   N, N-Dicyclohexyl-3- 4-(1,2-diphenyl-but-1-enyl)-phenyl!acrylamide;   N-(2-Dimethylamino-ethyl)-3- 4-(1,2-diphenyl-but-1-enyl)-phenyl!-N-ethyl acrylamide;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-N-methyl-N-octyl acrylamide;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!acrylamide;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-N-ethyl acrylamide;   1-Amino-3- 4-(1,2-diphenyl-but-1-enyl)-phenyl!-prop-2-ene-1-one oxime;   3-{2- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-vinyl}-5-methyl- 1,2,4!-oxadiazole;   3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-prop-2-ene-1-ol; and   {3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-allyl}-dimethylamine.   
     
     
       16. A method of treating a mammal for osteoporosis comprising administering to said mammal in need there at an effective amount of a compound according to claim 1. 
     
     
       17. A method of preventing osteoporosis in a mammal comprising administering to said mammal in need thereof an effective amount of a compound according to claim 1.